Project Summary/Abstract: Role of E3 Ligase, UBR5, in Hematopoietic Differentiation and Lymphomagenesis Mantle cell lymphoma (MCL) is a rare and aggressive non-Hodgkin's lymphoma. Unfortunately, limited therapies for MCL are currently available suggesting a need to further unravel molecular mechanisms regulating transformation and progression of the disease. The majority of MCL patients have mutations leading to overexpression of Cyclin D1 in the pre-B cell population, resulting in extensive proliferation and blocks in differentiation originating in the mantle zone of the lymph node. Recently, next generation sequencing has identified a number of novel mutations in MCL patients including the ubiquitin E3 ligase UBR5. E3 ubiquitin ligases serve as the substrate recognizing component for protein degradation by the ubiquitin proteasome system. Approximately 18% of MCL patients were found to have mutations within the HECT domain of UBR5, which can accept and transfer ubiquitin molecules to the substrate. Interestingly, in hematopoietic lineages the B-lymphoid populations including the pre-B cell compartment, highly express UBR5 compared to the myeloid and T-lymphoid compartments. These findings suggest that understanding the role and interacting proteins of UBR5 in hematopoiesis will provide insights to mantle cell lymphoma transformation, progression and possible future therapeutics targets, in addition to basic understanding of hematopoietic cell specification.